My sister has changed.
In Xiao Cen's memory, her sister began in her second year of high school and became different, "constantly drooling".
This embarrassed her sister, who asked Xiao Cen if she had similar symptoms, "I don't drool, I just don't speak clearly from novels, and I am always criticized by teachers and ridiculed by classmates."
At that time, the Xiao Cen family did not know that this may be a symptom of the rare disease Of Wilson's disease.
In 2020, xiao Cen sister went out to work when the tonsils became inflamed, and the symptoms of "cold, fever, cold body cold, sudden cold and hot" lasted for several months, and brain atrophy, mental retardation, suspected wilson disease were found in a municipal hospital in Jiangxi, and finally diagnosed at the First Affiliated Hospital of Sun Yat-sen University in Guangzhou.
Wilson's disease is a rare disease of autosomal recessive copper metabolism disorders in which patients form slow copper deposition in their organs, causing corresponding organ function and organic disorders.
In other words, patients with Wilson's disease are naturally unable to metabolize copper in the body, so they are in a state of "copper poisoning". Therefore, patients are also called "copper dolls".
Although it is a rare disease, it may be fortunate to have a copper doll (rare disease) – less than 5% of the world's about 7,000 rare diseases have effective treatment options, and patients often face the dilemma of high drug prices and unaffordable drugs.
Wilson's disease is one of the few neurogenetic diseases that can be treated at present, there is a mature treatment plan, and the commonly used drugs penicillamine tablets, dimercaptosuccinol capsules, and dimercapsulfa sodium injection are old drugs that have been on the market for many years.
The price of these drugs is low, and the current sales price of a single bottle / bottle ranges from 50 yuan to 259 yuan, which is one of the cheapest rare disease drugs.
However, it is these cheap drugs that have undergone several twists and turns in supply and security...
Recently, many copper doll patients have told the health community that the essential drug penicillamine is once again facing the situation of drug discontinuation and price increase. In the patient group, some people said negatively: "If you can't afford to take medicine, you can only wait for death."
According to the "Guidelines for the Diagnosis and Treatment of Wilson's Disease" compiled by the Neurology Branch of the Chinese Medical Association, the recommended principle for the treatment of Wilson's disease is lifelong treatment in the absence of liver transplantation.
This means that without a stable supply of medicines, patients may survive uncertainty for the rest of their lives.
Discontinuation of the drug
The first time to find out of medicine, it was because the commonly used drug purchase channel was out of medicine. Chen Bing, founder of the Copper Doll Rare Disease Care Center (Hepatupa Association), told the health community that at that time, "some domestic pharmacies could not buy it."
A patient from Sichuan told the health community that penicillamine could no longer be bought in many parts of his sichuan province. Moreover, in Sichuan Province, the authoritative medical institution for Wilson's disease, the West China Fourth Hospital of Sichuan University, has also been discontinued.
The health community called the pharmacy outpatient department of the hospital as a family member, and the pharmacy staff said that because the manufacturer had not yet produced, penicillamine had been out of medicine for a while, and when the supply would be restored, it was not known.
This is not the first time that penicillamine has been discontinued. In 2016, due to the lack of raw materials, the only domestic penicillamine manufacturer "Shanghai Xinyi Pharmaceutical" could not supply penicillamine, resulting in a large-scale outage of penicillamine nationwide, and triggered a large public controversy in 2017.
In March 2020, due to the shortage of raw materials, the dicaptopropanesulfon sodium injection was exposed to discontinuation, and the supply was gradually restored until November of that year. However, after the resumption of supply, the price of erthiopropanesulfonate injection rose from 59 yuan / stick in 2020 to 98 yuan / stick, and patients complained bitterly for a while.
Therefore, after the small-scale discontinuation of the drug, some patients are worried about whether this is a "precursor" to the upcoming price increase of penicillamine? In the end, this speculation was confirmed on the official mini program of Xinyi Pharmacy.
In early January 2022, Xinyi Pharmacy Mini Program issued a notice saying that the new batch of penicillamine arrived in mid-January 2022, and the price of 50 bottles / capsule was 103.5 yuan. This price is 2.27 times the previous price of Xinyi Pharmacy (90.9 yuan / bottle / 100 tablets), and it is also 2.62 times the national matching price (79 yuan / bottle / 100 tablets). On the external platform, penicillamine sold 50 tablets for 98 yuan and 2 boxes of 50 pieces of penicillamine for 251 yuan.
Shanghai Xinyi is the only manufacturer of penicillamine so far. According to its official WeChat public account, "Xinyi Pharmacy is a branch of Shanghai Xinyi Tianyi Pharmaceutical Co., Ltd." This also means that the conjecture of the previous price increase of penicillamine has been basically confirmed.
This makes the patient nervous for a while. Everyone has inquired about the latest purchase price of penicillamine, and even in the patient group, there is a statement that "the in-hospital sales price of penicillamine may be raised to 158 yuan / bottle / 50 capsules".
The health community has learned through multi-party verification that the price increase of penicillamine is indeed a matter. The latest hanging net price of penicillamine is 90 yuan / bottle / 50 capsules, and the price of a single bottle is basically the same as in the past, but the dosage is less than half.
In addition, in response to the packaging change problem that patient groups are concerned about, some sources revealed to the health community that it is mainly clinical drug needs and safety considerations. "Penicillamine is used in about 50 tablets a week, as an old medicine, how to ensure the quality of the drug after the icing tablets are opened?" This is also the need that the clinic has responded to the pharmaceutical companies." For medication safety reasons, the latest batch of penicillamine is adjusted to 50 tablets/bottle. But in the future, 50 tablets and 100 tablets of penicillamine will remain consistent in the price system.
Although the increase was not as high as speculated, it was still difficult for patients to accept for a while.
"The price increase is understandable, but it has risen so much at once, and for those who do not have a job and cannot take care of themselves, it is simply a disaster." Patient Zhou Bo told the health community.
Zhou Bo is an old patient who has survived on penicillin for most of his life, "I have eaten since 83, and I have eaten it for almost 40 years now, about 1,78 bottles, and there may be a car."
The price changes of penicillamine in the past four decades can be described by Zhou Bo. "From 4 yuan in 1983 to 89 yuan, then to more than 30, more than 60, more than 90, and now 103 yuan (actually 90 yuan / bottle) 50 pieces."
"The biggest price increase was from 89 yuan to more than 30 yuan. From the 1990s to the present, there has been little change in the price of penicillamine in the past 30 years. Before, because of the state matching price, it also fell, 79 yuan / bottle." Zhou Bo recalls.
indissoluble
The main controversy over the price increase of drugs is the speed and magnitude of the price increase. In this regard, patient Lily described, "In recent years, drug prices have been rising in a helicopter, and there is no respite."
Taking the sodium dithene sodium injection as an example, in 1996, the drug was 2.7 yuan / stick, and after it rose to 8 yuan in 2000, the price remained unchanged for 10 years. It rose to 15 yuan in 2010 and 29 yuan in 2018, which almost doubled in 8 years. From 2020 to 2021 alone, it will rise from 50 yuan to 98 yuan, an increase of 96%.
The price changes of essential drugs for Wilson's disease are counted according to the medical reimbursement forms of patients over the years
"The reason given by the manufacturers is that the price of raw materials has increased, but I think that raw materials only account for a small part of the pharmaceuticals and cannot constitute such a high increase." Patients with Wilson's disease Yang Yang believe.
Even some patients believe that the price increase of dithiopropanesulfon sodium injection in 2020 and penicillamine in 2022 began after the drug was discontinued to restore supply, and it is not excluded that pharmaceutical companies "hunger marketing" and take some "means" to increase the price of drugs.
For similar doubts, pharmaceutical companies usually feel "wronged".
Zhang Jie, the person in charge of a small variety of drugs (shortage drugs), told the health community that the cost of pharmaceutical companies cannot simply be superimposed on rent, raw materials, labor, depreciation, circulation, etc. Especially for shortage drugs with low clinical dosage, in order to ensure supply, pharmaceutical companies often have to pay a lot of hidden costs.
Taking the price increase of raw materials as an example, Gu Haoliang, vice president of Shanghai Pharmaceutical and chairman of Shanghai Pharmaceutical Xinyi, once said in an interview with the media: "Shanghai Pharmaceutical Xinyi signed a ten-year agreement with Jiangxi Dongfeng Pharmaceutical Co., Ltd. to invest 10 million yuan to build a new independent workshop for APIs, which completely solved the shortage of penicillamine tablets."
"Even if these costs are diluted to a 10-year contract period, they are not small amounts per year." Zhang Jie said. The annual sales of penicillamine are only more than 10 million yuan, and the new API independent workshop alone may increase the annual cost of nearly one million.
As for the patient's feedback on the drug cut, the health community learned through multi-party verification that this is only a local situation, not a real shortage. In fact, pharmaceutical companies have been producing supplies normally.
"This time, the patients reported that the drug was cut off, mainly referring to the hospital channel." A person close to the circulation channel of penicillamine said that if patients cannot prescribe drugs in the hospital, they can also go to the medical insurance pharmacy to buy; if the medical insurance pharmacy cannot buy, Xinyi Pharmacy and other online sales channels also have drug supply.
The health community has learned that the first batch of new packages of penicillamine in Xinyi Pharmacy have arrived in mid-January and sold out. The second batch also arrived on January 20 and is currently in sufficient quantities.
The discontinuation of the hospital channel is mainly due to the need to re-hang the net to enter the hospital after the replacement of the penicillamine packaging. Chen Shicai, chief pharmacist of Beijing Luhe Hospital affiliated to Capital Medical University, said that changes in drug specifications require pharmaceutical companies to re-examine the application and hang up the network, which may take a long time. For non-winning products, it is necessary to re-negotiate the price with the hospital. If hospitals have other alternatives and are unwilling to negotiate, new packaged drugs cannot be hung up.
The health community learned through exclusive channels that the newly packaged penicillamine has been hanging up the network program in various places at the end of 2021, and some provinces have been rapidly advancing, and it is expected that after the Spring Festival, the supply channels in the hospital will be restored one after another.
The Affiliated Hospital of the Institute of Neurology of Anhui University of Traditional Chinese Medicine (hereinafter referred to as "Anhui Shen research institute"), which has the largest diagnosis and treatment of Wilson's disease in China, has been in normal supply. Patients who are hospitalized have reported that "the hospital has a large amount of medication, stocks, and treatment has not been affected."
oppugn
After communicating with patients for many years, Changjiang learned about the economic difficulties of many patients in taking drugs. In the face of this price increase, Yangtze felt that something should be done for patients. So he asked the local municipal government through 12345 to supervise the rationality of the price increase of penicillamine.
He wanted to figure out why a clinical necessity drug, which had been stable for many years, would rise sharply at the beginning of this year.
Trace the reasons for price increases, or both practical dilemmas and historical reasons.
The real dilemma is the supply of raw materials. Since 2015, the supply of penicillamine raw materials in the country has been hindered by compliance issues such as environmental protection. To this end, the production enterprise has entrusted Jiangxi Dongfeng Pharmaceutical Co., Ltd. to customize the production of 4 tons of penicillamine API, which is about 2-3 years of dosage.
"The price of custom production is definitely not the same. Moreover, in recent years, the requirements of the state in terms of drug quality standards have been increased several times. Every time the standard is raised, it means that raw material suppliers have to spend more efforts to improve the quality of raw materials, and the price of RAW Materials has risen dramatically." In addition, the person familiar with the matter said that with the improvement of national environmental protection requirements in recent years, the production costs of pharmaceutical companies have continued to increase.
"Environmental protection requires that the fermentation of penicillamine APIs requires independent workshops, independent environmental protection treatment, and even emissions are independent. These costs are borne by Shanghai Pharmaceutical when the price of penicillamine has not yet increased. Because there is currently only one manufacturer in the country that can produce penicillamine APIs. If they don't do it, Shanghai Medicine can't do penicillamine no matter how capable it is."
The historical reason for this price increase may be related to the abnormally low price of cheap drugs for rare diseases.
The health community has exclusively learned that the price of penicillamine of 79 yuan / bottle / 100 tablets in the past is "government-matched price", which has not changed for many years. However, in recent years, with the increase in production costs, the improvement of pharmaceutical processes, the increase in raw material prices and other factors, the price of penicillamine has been seriously inverted, and the production cost is now much higher than the selling price. Therefore, this price adjustment is a reasonable price adjustment under the circumstances permitted by the state, with the purpose of returning penicillamine to a reasonable price and not allowing enterprises to produce a batch of losses.
He Bin, a special researcher at the Public Policy Research Center of the Institute of Economics of the Chinese Academy of Social Sciences, shared the factors that may affect the price increase of drugs from an economic perspective. "There are many controls and regulations in the production process of drugs, and pharmaceutical companies also need to invest huge amounts of money in order to comply with the law, which are also costs, and the more important factor affecting prices is supply and demand."
He Bin believes that when discussing corporate social responsibility, it is first necessary to understand that only living enterprises can fulfill their social responsibilities, and enterprises that allow themselves to lose their competitive advantages will often go bankrupt, and the main body that fulfills social responsibilities does not exist, so enterprises must first "survive" and then provide valuable drugs and employment opportunities to the society, which is the greatest social responsibility of enterprises. "Whoever makes less money will lose their competitive advantage, which is a business factor that companies have to consider." And "good intentions" that ignore objective laws often lead to tragedy."
Considering the perennial low price of cheap old drugs such as penicillamine, He Bin believes that "price increases may also be a return to a reasonable price, and all unreasonable low prices cannot be taken as standards."
Guaranteed Supply
In 2017, penicillamine API factory underwent GMP (Good Manufacturing Practice) transformation and suspended supply, resulting in the suspension of penicillamine production. Chen Bing recalled, "The initial suspension was planned, but I didn't expect the market to be so sensitive. Considering that penicillamine is a life-saving drug, Xinyi Pharmaceutical Factory quickly contacted a raw material manufacturer in Sichuan to urgently restore supply."
However, because the raw material particle size of the new raw material manufacturer is different from the raw material that has been used before, it cannot adapt to the production process of penicillamine tablets, and the tablet pressing is abnormal during production. This has led to the dilemma of penicillamine facing a sharp drug cut.
Coincidentally. In 2020, the second mercaptopropane sodium injection was discontinued, also because of the environmental protection upgrade of its raw material manufacturer "Shanghai Wanxiang".
According to media reports, due to the increase in environmental protection requirements, in 2016, Shanghai Wanxiang began to try new environmental protection process development, and in early 2017, the old process API was discontinued. However, due to the high difficulty of process research and development and the increase in national supervision, the time to finally complete the research and development of new process APIs is slightly later than expected. This directly led to the stagnation of the production of dimercapsulfa sodium injection, and the supply cut lasted for about half a year.
Each time is a pre-planned upgrade, but in the end it affects the medication of the patient group. The fragility of the supply chain of cheap drugs for rare diseases is evident.
When it comes to the reasons, it is mainly due to the low price and low use of cheap drugs for rare diseases, and the lack of production power of RAW Materials and Pharmaceutical Preparation Manufacturers. Some drugs may be the only pharmaceutical company in the country with production capacity, resulting in a problem to ensure supply.
Why are pharmaceutical companies reluctant to cut into the production of shortage drugs? The key lies in the unequal relationship between cost and output.
Zhang Jie calculated the account for the health community: "Invest in a penicillamine production line, and the workshop will be at least 40 million to 50 million." If you want to declare drug registration, a generic drug declaration of 10 million is already relatively economical. Then, you have to have your own channels and sales team, right? What is the final output? More than 10 million sales a year? And there is almost no profit, and drug prices have been upside down in the past. Do you think there will be companies willing to invest tens of millions of dollars to make such a product?"
In order to achieve a shortage of drug supply, in 2018, the Ministry of Industry and Information Technology and relevant departments jointly identified 6 key domestic enterprises to lead the formation of a consortium to carry out the construction of a centralized production base for small varieties of drugs. By the end of 2020, the Shanghai Pharmaceutical and Pharmaceutical Federation alone has achieved a guaranteed supply of 32 varieties.
In 2020, Shanghai Pharmaceutical established a wholly-owned subsidiary, Shanghai Pharmaceutical Ruier, to carry out the development of rare disease drugs that are urgently needed clinically, supply shortage, precise efficacy, patent expiration and global innovation.
The health community understands that there are already four market holders of clinical shortage drugs for rare diseases transferred to the innovation platform of Shangyao Ruier. In addition to the essential drugs "penicillamine" and "dimerbuctic acid capsules" used to treat Wilson's disease, there are also "tretinoin tablets" and "brombistine tablets".
The above drugs are all cheap old drugs that are urgently needed clinically and have exact efficacy, and have previously been discontinued due to insufficient production power or shortage of raw materials by pharmaceutical companies. After the transfer of the listing holder, the drug supply guarantee work will be completed by Shangyao Ruier.
A person close to Shangyao Ruier revealed that in order to do a good job in ensuring the supply of drugs, Shanghai Pharmaceutical has paid a lot of energy to stabilize the supply chain, and is closely bound with raw material manufacturers to ensure supply.
guarantee
Drug supply and product upgrades, and it is the patients who ultimately benefit. Although Wilson's disease cannot be cured, after formal treatment, most patients can study, live and work normally.
After the resumption of production due to environmental protection transformation and technological upgrading, the quality of drugs has been significantly improved. According to Chenbing's survey of the patient group, on the one hand, the number of people who are allergic because of taking the drug is greatly reduced, on the other hand, the drug is more powerful, "For example, it was necessary to use 6-8 copper water, and now 5-6 may be enough." Therefore, in his view, "the marginal cost of medical treatment has decreased, and it is understandable that the price increase of pharmaceutical companies is not too fierce."
Guaranteed supply and product upgrades will inevitably bring about an increase in the cost of pharmaceutical companies. Therefore, vigorously promoting the reasonable reimbursement of Wilson's disease within the scope of medical insurance can truly and effectively reduce the medical burden on patients.
The three drugs commonly used in the clinical trial of copper dolls are in the medical insurance class A catalog, which is a medical insurance reimbursement drug. According to the 2021 China Medical Security Statistical Yearbook, in 2020, the medical insurance fund for hospitalization expenses within the scope of the employee medical insurance policy will pay 85.2%, and the hospitalization expense fund within the scope of the resident medical insurance policy will pay 70.0%. If medical expenses can be reimbursed proportionally, the burden on patients will be greatly reduced.
However, in the actual guarantee, some blockages cause patients to have to pay out of pocket, which makes them extremely sensitive to drug prices.
The first is the difficulty of hospitalization. There are only a few hospitals in the country that can do inpatient copper expulsion treatment for patients with Wilson's disease, and the more well-known ones are the Institute of Divine Research in Hefei, Anhui, the Second Affiliated Hospital of Zhejiang University School of Medicine, and the West China Hospital of Sichuan University. Most of these hospitals are concentrated in first-tier cities, and patients are often scattered throughout the country. This means that most patients have to seek medical attention in a different location.
The reimbursement rate for off-site medical treatment is relatively low, and referral or advance filing is required. The actual reimbursement rate of residents is not high.
The second is the difficulty of prescribing drugs on outpatients. Home medication is one of the daily control methods for patients with Wilson's disease. If you count as 6-8 capsules of penicillinine per day for adults, 100 capsules of packaged medicines are only enough to eat for 12-18 days. Patients are hospitalized once, often carrying drugs for no more than 2 weeks. The low rate of outpatient reimbursement and the low annual amount is equivalent to the fact that the patient may have to pay out of pocket.
In recent years, some localities are trying to include penicillium, an essential drug for Wilson's disease, in outpatient chronic disease (special disease) reimbursement. This can greatly reduce the burden of reimbursement for patients.
However, due to the small amount of drugs used for rare diseases, most hospitals may not have stockpiles at all, and outpatient chronic diseases need to be reimbursed after identification, and there are very few doctors who can diagnose rare diseases, and patients may not be eligible for reimbursement at all.
Da Liu is a patient with Wilson's disease in Luohe, Henan. Luohe is one of the few cities in Henan Province that includes Wilson's disease in outpatient chronic diseases. Fortunately, he had policy support, but he never received outpatient chronic disease reimbursement.
"When I applied in 2021, the hospital checked that I was cirrhosis and did not meet the reimbursement rules, so the application was not successful." Da Liu can only buy penicillamine through ordinary outpatient clinics, and the reimbursement amount is extremely low.
Knowing that the price of penicillamine has risen again, Da Liu's mother said that she was helpless, "There is no way, the medicine is too expensive, but it is not okay to eat it." The Da Liu family could only rely on seven or eight acres of land and cobbled together to borrow money to maintain treatment.
Da Liu hopes that the local policy can be opened up as soon as possible, so that he can enjoy the reimbursement of the outpatient chronic disease policy. In this way, it can also reduce some of the burden on the family...
(In order to protect the privacy of the interviewees, except for Chen Bing, Chen Shicai, and He Bin, the rest are pseudonyms.) ）
Resources:
1. Wilson's Disease, edited by Yang Renmin, People's Medical Publishing House
2. 300 days of drug discontinuation This group of patients with unsettled rare diseases cried and said that they did not want to die, Chengdu Business Daily, https://www.sohu.com/a/134552321_617717
3. The life-saving drug "dithomethanesulfon sodium" is difficult to find, Health Times, https://baijiahao.baidu.com/s?id=1675262866055393791&wfr=spider&for=pc
4. "Dimercaptosulfon sodium" is out of stock and the price is rising! Pharmaceutical companies responded: API prices rose, China Fortune Network, https://baijiahao.baidu.com/s?id=1688652937420677485&wfr=spider&for=pc
5. Feature |" Copper doll "behind the drug discontinuation storm The only API company stopped production, Caixin Health, http://oppo.yidianzixun.com/article/0PfA8Nvt?s=oppobrowser&appid=oppobrowser&impid=-1134756418_1592747875257_0LeoFNZi_n2n&__publisher_id__=8IrpHp87M0nZJcwzFTi2ww
6. Common clinical classification of Wilson's disease, http://www.wilson-disease.org/sitecn/cjfx/628.html
7. Shanghai Small Variety Drug Consortium has realized the production and supply of 100 small varieties of drugs, People's Daily and https://baijiahao.baidu.com/s?id=1700801549109900027&wfr=spider&for=pc
Sources | the health community
Written by | and stars
#家庭健康守护官 #